title: GSTT1 null and MPO -463G>a polymorphisms and carboplatin toxicity in an Indian population.
abstract: Carboplatin, a second generation platinum drug, is widely used to treat different types of cancers. However, myelosuppression remains a major consideration in its use. Genetic polymorphisms of enzymes involved in drug disposition can influence therapeutic outcome. The homozygous null deletion of phase II metabolic gene GSTT1 that abolishes its xenobiotic- detoxifying ability may be associated with carboplatin toxicity. Further, since carboplatin generates oxidative stress, polymorphisms of oxidative stress genes that regulate the cellular level of free radicals may have important roles in generating drug- related adverse effects. We here investigated the null polymorphism of GSTT1, and the -463G>A promoter polymorphism of oxidative stress gene myeloperoxidase (MPO) for carboplatin toxicity in a population of northern India. Cancer patients who were treated with carboplatin, and developed toxicity was considered. The study group comprised of 10 patients who developed therapy- related adverse effects. Peripheral blood was taken from patients for DNA isolation. GSTT1 null genotype was determined by conducting duplex PCR and MPO-463 G>A was determined by PCR followed by RFLP. Hematologic toxicity was experienced by 5 patients, 2 of them had grade 3 and 4 toxicity and 3 others had grade 2 toxicity. They also had gastrointestinal (GI) toxicity. Remaining 5 individuals developed GI toxicity but no hematological toxicity. While GG homozygous of MPO was present in majority of patients having hematologic toxicity (in 4 out of 5 individuals), one A allele (AG genotype) was present in 4 patients who did not have any hematological toxicity. Thus variant A allele of MPO -463G>A may be related to lower hematological toxicity. These preliminary data, however, are required to be confirmed in larger studies along with other relevant polymorphisms.
authors.affiliation: Institute of Allied Health (Paramedical) Services, Education and Training, Govt. Medical College , Haldwani, Uttarakhand, India E-mail : arundhatis5@rediffmail.com.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Bag
authors.forename: Nirdosh Kumar
authors.initials: NK
authors.lastname: Pant
authors.forename: Lalit Mohan
authors.initials: LM
authors.lastname: Jeena
authors.forename: Niladri
authors.initials: N
authors.lastname: Bag
authors.forename: Narayan Singh
authors.initials: NS
authors.lastname: Jyala
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects*; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006402:Hematologic Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007194:India / Q000453:epidemiology; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D009195:Peroxidase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D009195:Peroxidase; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase